Hypothesis: The female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating x chromosome on the molecular mechanisms of neural fold elevation

Abstract

Females have long been known to be in excess among cranial neural tube defect (NTD) cases. Up to two thirds of human anencephalics and mouse exencephalics from various genetic causes are female, but the cause of this female excess is unknown. It appears not to be attributable to gonadal hormones, developmental delay in females, or preferential death of affected males. Recent studies of the Trp53 mouse mutant showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y. Over a decade ago, we hypothesized that the relevant difference between female and male mammalian embryos at the time of cranial neural tube closure is the fact that females methylate most of the DNA in the large inactive X chromosome after every cell division, reducing the methylation available for other needs in female cells. Recently, the Whitelaw laboratory identified several proteins in mice (Momme D genes) involved in epigenetic silencing and methylation and shared in the silencing of transgenes, retrotransposons, and the inactive-X, and suggested that the inactive-X acts as a "sink" for epigenetic silencing proteins. The "inactive-X sink" hypothesis can be used to suggest expected changes in sex ratio in cranial NTDs in response to various genetic or environmental alterations. We recommend that observation of sex ratio become a standard component of all NTD studies. We suggest that the female excess among cranial NTDs is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying NTDs.

Maternal and Infant Factors Associated With Infancy-Onset Hydrocephalus in Washington State

“…While the findings presented here are based on relatively few cases and are therefore imprecise, it is noteworthy that this finding is consistent with reports from multiple previous studies 14, 15 . We believe this primarily reflects the increased risk of intraventricular hemorrhage seen in male preterm infants, which has been well described 16–18 .…”

Spina bifida

“…In twins, the concordance for NTDs is higher amongst same-sex twin pairs (monozygotic and dizygotic) than opposite-sex twins (only dizygotic). The finding of a female excess among fetuses/infants with anencephaly, but not with spina bifida, has strongly suggested a sex-related genetic or epigenetic relationship 14. Finally, the NTD prevalence differences between ethnic groups have been reported to persist in some cases after migration to other geographical locations 15.…”

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

“…Overexpression of escapees may not be the only mechanism by which an inactive X contributes to autoimmune disorders. The inactive X has been proposed as a sink for heterochromatic silencing proteins [128,129], potentially altering the capacity for females to silence or maintain silencing in the presence of additional sequence variations or cellular stresses. Hypomethylation is a general feature of lupus, and other autoimmune disorders (reviewed in [130]).…”